Alzheimer's Disease (AD) is a degenerative brain disorder presented clinically by progressive loss of memory, cognition, reasoning, judgement, and emotional stability that gradually leads to profound mental deterioration and ultimately death. Individuals with AD exhibit characteristic beta amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles. On autopsy of AD patients, large numbers of these lesions are generally found in areas of the human brain important for memory and congnitive function. Smaller numbers are found in the brains of most aged humans not showing clinical symptoms of AD. Beta amyloid plaques and beta amyloid angiopathy also characterize the brains of individuals with Down's Syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage with Beta amyloidosis of the Dutch-Type, and other such disorders.
Beta amyloid plaques are a defining feature of AD, now believed to be a causative precursor or factor in the development of disease. Beta amyloid plaques are predominantly composed of beta amyloid beta peptide (Aβ, also sometimes designated βA4).
Several isotypes of APP are known to date, including “normal” APP-695, APP-751, and APP770, having a sequence of 695, 751, and 770 amino acids, respectively. The identification of mutations in the beta amyloid precursor protein gene that cause familial, early onset AD implicate beta amyloid metabolism in the pathology of the disease. Such reported mutations include the double Swedish mutation (SW), changing Lys595 and Met596 to Asp595-Leu596, and mutations altering Val717 to Gly, Ile, or Phe.
Aβ peptide is derived by proteolysis of the beta amyloid precursor protein (APP) and is comprised of 39–42 amino acids. Several proteases called secretases are involved in the processing of APP. Deposition of Aβ in areas of the brain responsible for cognitive activities is a major factor in the development of AD. Cleavage of APP at the N-terminus of the βA4 peptide by β-secretase and at the C-terminus by one or more γ-secretases constitutes the beta amyloidogenic pathway, i.e. the pathway by which Aβ is formed. Cleavage of APP by β-secretase and the same or a different γ-secretase produces α-sAPP, a secreted form of APP that does not result in beta amyloid plaque formation. This alternate α-sAPP pathway precludes the formation of Aβ peptide. It has been proposed that Aβ accumulates as a result of processing of APP by β-secretase, and that therefore inhibition of the activity of this enzyme is desireable for the treatment of AD. In vivo processing of APP at the β-secretase site is thought to be the rate-limiting step in Aβ production, and is thus a therapeutic target for the treatment of AD. See, for example, Sabbagh et. al., 1997, Alz. Dis. Rev. 3:1–19). A description of the proteolytic processing fragments of APP can be found, for example, in U.S. Pat. Nos. 5,441,870, 5,721,130, and 5,942,400.
Several lines of evidence indicate that progressive cerebral deposition of particular beta amyloidogenic peptides, β-amyloid peptides, (Aβ), play a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, 1991, Neuron 6:487. Recently, it has been shown that Aβ is released from neuronal cells grown in culture and is present in cerebrospinal fluid (CSF) of both normal individuals and AD patients. See, for example, Seubert et al., 1992, Nature 359:325–327.
An aspartyl protease has been identified as the enzyme responsible for processing of APP at the β-secretase cleavage site. The β-secretase enzyme has been disclosed using varied nomenclature, including BACE and Asp. See, for example, Sindha et. al., 1999, Nature 402:537–554 (p501) and published PCT application WO00/17369 (hAsp2a and hAsp2b).
At present there are no effective treatments for halting, preventing, or reversing the progression of Alzheimer's disease. Therefore, there is an urgent need for pharmaceutical agents capable of slowing the progression of Alzheimer's disease and/or preventing it in the first place.
Compounds that are effective inhibitors of β-secretase, that inhibit β-secretase-mediated cleavage of APP, that are effective inhibitors of Aβ production, and/or are effective to reduce beta amyloid beta deposits or plaques are needed for the treatment and prevention of disease characterized by beta amyloid beta deposits or plaques, such as AD.